The microtubule associated protein tau is essential for development and maintenance of the nervous system. On the other hand, tau dysfunction has long been correlated with Alzheimer's disease pathology. Further, recent genetic evidence demonstrates that mutations affecting either the primary structure of tau or the regulation of tau RNA alternative splicing lead to pathological tau fiber formation similar to that observed in Alzheimer's disease, neuronal cell death and FTDP-17, a collection of human dementias. Gaining a thorough understanding of tau action is therefore an important goal. At a mechanistic level, tau serves its many functions by regulating microtubule dynamics, that is, the growth, shortening and movement of microtubules. This application examines the manner in which tau affects microtubule dynamics under both normal and pathological conditions. These investigations will define the molecular mechanisms by which normal tau regulates microtubule dynamics, and then test the hypothesis that mutations in the tau gene that are linked to neuronal cell death and neurodegenerative disease alter the quantitative and/or qualitative manner by which tau regulates microtubule dynamics. In addition, we will begin to test the hypothesis that modifications in taus ability to regulate microtubule dynamics resulting from the structural and regulatory tau mutations can contribute to neuronal degeneration.